The long-term goal of the Lymphoid Development and Malignancy (LDM) Program is to improve outcomes and seek cures for patients with lymphoid malignancies, including acute lymphoblastic leukemia (ALL) and B cell non-Hodgkin lymphoma (B-NHL). The Program is motivated by the notion that new therapeutic modalities of high efficacy and low toxicity can be developed by specifically targeting the altered oncogenic pathways of malignant cells. To achieve this end, the following Specific Goals will be pursued: 1. Identify major cellular pathways that regulate the development of lymphoid tissues. Molecular .biology, genetic and systems biology approaches will be used to elucidate cellular pathways that regulate the growth, survival and differentiation of immature lymphocytes (the precursors of ALL) and mature B cells (the precursors of B-NHL). 2. Identify genes and pathways involved in the pathogenesis of lymphoid malignancies. In particular, the genetic lesions and deregulated cellular pathways that are casually associated with the pathogenesis of ALL and B-NHL will be identified. 3. Develop novel therapies that target the deregulated cellular pathways of lymphoid malignancies. Known drugs as well as compounds identified through screening approaches will be tested as single agents and in combinations for their ability to target deregulated pathways in lymphoid malignancies using pre-clinical models and Phase I/I I clinical trials. The LDM Program consists of 28 members (17 full members, 5 clinical members, and 6 associate members) from 10 departments within the College of Physicians &Surgeons at Columbia University, as well as 4 members from the Weill Cornell Medical Center. The Program is supported by large program project grants, including a Leukemia Lymphoma Society Specialized Center of Research (SCOR) grant on "Molecular Targets in Lymphoma" and a grant from the National Center for multi-scale study of Cellular Networks. For the last budget year of the grant (July 1, 2006 - June 30, 2007), the LDM Program received a total of $10.4M (direct costs) in cancer-relevant grant support, including $3.6M (direct costs) in NCI funding, $4.3M (direct costs) in other cancer-related peer-reviewed funding, and $2.5M (direct costs) in cancer-related non-peer-reviewed funding. The total number of cancer-related publications since the previous submission (i.e., 2003-present) was 202, of which 12.9% were intra-programmatic and 10.4% inter-programmatic.